The field of the present invention relates to methods and devices for the treatment of gastro-esophageal reflux disease (abbreviated as GERD, also abbreviated as GORD for the British spelling gastro-oesophageal reflux disease).
GERD is a disease in which there is reflux (back-flow) of acidic fluid, pepsin, and other injurious substances from the stomach to the esophagus. Initially, the reflux does not erode the esophagus, and the patient is said to have non-erosive reflux disease (NERD). However, when it occurs frequently and over an extended period of time, the reflux damages the mucosal lining of the esophagus. Untreated disease may then progress to erosive esophagitis, pre-cancerous Barrett's metaplasia, or adenocarcinoma of the esophagus.
Thus, GERD is a spectrum of diseases, experienced by many patient subgroups that share the common symptom of reflux. Approximately 10-20% of all individuals in the Western world suffer from GERD, defined by at least weekly significant heartburn and/or acid regurgitation events. In the United States the prevalence is 15-20%, while in Asia the prevalence is less than 5%. Nearly half of the affected individuals report experiencing symptoms for more than 10 years. GERD is often co-morbid with, and may aggravate or be aggravated by: abdominal pain, dysphagia, dyspepsia, asthma, cough, hoarseness, angina, gall bladder disease, laryngitis, otitis, sinusitis, chest pain, and anxiety/depression. The prevalence of GERD increases with age.
The most important factor contributing to the onset of GERD is failure of the anti-reflux barrier that separates the stomach from the esophagus, at the gastro-esophageal junction. The anti-reflux barrier contains two major components: the lower esophageal sphincter (LES) and the crural diaphragm. The LES is sometimes referred to as the “intrinsic” LES, to distinguish it from the crural diaphragm that is sometimes referred to as the “extrinsic LES”. The (intrinsic) LES is a ring of muscle within the lower end of the esophagus that spends much of its time in a contracted state, essentially closing the esophageal lumen at that location, thereby providing a mechanical barrier between the stomach and esophagus. The LES is best identified functionally with pressure sensors as a high-pressure zone, surrounding the lumen of the esophagus in its terminal 2 to 4 cm, that relaxes reflexively for about 8 seconds upon swallowing. The LES is often, but not always, thickened relative to the esophageal muscle above it.
The part of the stomach that is attached to the esophagus is known as the cardia. The LES and cardia overlap anatomically but are physiologically distinct in that the LES exhibits reflex relaxation. The angle of His is the acute angle between the esophagus and cardia at the entrance to the stomach. The magnitude of this angle affects the ease with which the contents of the esophagus may pass into the stomach, and vice versa, known as a “flap-valve” effect.
The diaphragm is a muscle that separates the abdomen from the thorax, best known for its role in the mechanics of breathing. A series of apertures within the diaphragm allow the passage of structures between the thorax and abdomen, and the esophagus passes through one of those apertures. In normal individuals, the right crus of the diaphragm is attached circumferentially to the LES by the phreno-esophageal ligament, and this encircling attachment provides additional mechanical support to the LES. Thus, in normal individuals, contraction of the crural diaphragm muscle is concentric with contraction of the muscle of the LES, so the pressure in the terminal portion of the esophageal lumen that is due to muscular contraction of the LES is superimposed upon that which is due to the contraction of crural diaphragm muscle. The sphincter-like contraction of the crural diaphragm increases during inspiration when there is increased abdominal pressure. That increased abdominal pressure tends to promote reflux, but contraction of the crural diaphragm counteracts that tendency.
However, in individuals that have the most common form of hiatal (or hiatus) hernia, the proximal stomach protrudes (prolapses) through the diaphragm, moving the proximal stomach from its normal position in the abdomen and into the thorax. This also moves the LES upwards from the plane of the diaphragm upwards into the thorax. This type of hernia is known as a sliding hiatal hernia, and it appears to be due to a loss of elasticity of the phreno-esophageal ligament that connects the crural diaphragm to the LES, plus a shortening of the esophagus that occurs even normally due to contraction of the longitudinal esophageal muscles after swallowing. The herniated part of the stomach may slide up and down, into and out of the chest. However, if the hernia is large, it may remain within the chest at all times, it which case it is called a fixed or permanent hiatal hernia.
When a hiatal hernia is present, muscular contraction of the (intrinsic) LES is no longer concentric with contraction of the crural diaphragm. Consequently, if luminal pressure measurements are made from the terminal end of the esophagus to the proximal portion of the stomach, two high pressure zones may be measured in individuals with a sliding hiatal hernia—one pressure zone corresponds to the (intrinsic) LES at the gastro-esophageal junction, and the other pressure zone is located below the herniated sac of stomach where the diaphragm now encircles the proximal stomach. Considering that a hiatal hernia changes the mechanics of the anti-reflux barrier, its presence contributes to the onset of GERD. However, the nature of that contribution has long been controversial, due to the multiplicity of other interacting factors that contribute to GERD, as now described.
When both components of the anti-reflux barrier are functioning normally, the lumen of the lower end of the esophagus ordinarily has a pressure that varies from 15-30 mmHg greater than pressure within the stomach. Variations in the LES pressure over that range occur in conjunction with muscle contractions of structures to which the LES is attached, namely, the part of the esophagus that lies above it and the stomach. When the muscle of the LES relaxes, peristaltic bolus pressure, gravity, and residual tension and elasticity of the LES force ingested food, liquids, and swallowed air from the esophagus into the stomach. When the muscle of the LES subsequently contracts, any food remaining in the LES is squeezed into the stomach, and after closing, the LES once again provides a mechanical barrier between the esophagus and stomach by resisting distension. Pressure is also contributed by the crural diaphragm (extrinsic LES), and that pressure varies as a function of breathing, posture, abdominal pressure, coughing and the like. However, the LES is not a one-way valve, because gasses that form in the stomach subsequent to a meal must be vented through the LES in the form of belches, as indicated below.
The state of contraction of the muscle of the LES, as well as the state of contraction of the muscles of the crural diaphragm, are controlled by nerves to those muscles, as well as by local factors including hormones, drugs, and food chemicals. In normal individuals, the LES relaxes reflexively (and the LES luminal pressure decreases) following swallowing and following the peristalsis of the esophagus that accompanies the passage of food. That relaxation makes possible the passage of food and liquids through the opening of the LES, at a rate that is determined by the instantaneous pressure difference between the LES lumen and stomach.
Three mechanisms leading to reflux are now described—TLESR, stress reflux, and LES hypotension.
Unless progression of GERD has reached erosive esophagitis or Barrett's metaplasia, the resting tension of a patient's LES is ordinarily in the normal range (i.e, normotensive). In the case of a normotensive LES, the problem is usually not one of persistent back-flow of the contents of the stomach to the esophagus. Instead, the predominant mechanism of gastroesophageal reflux is transient lower esophageal sphincter relaxation (TLESR). With TLESR, the LES relaxes spontaneously, briefly, and episodically without prior swallowing or esophageal peristalsis. TLESR is caused by control of LES relaxation by the nerves that provide feedback to modulate the state of relaxation and contraction of LES muscle. The feedback is mediated by the vagus nerve, and is often associated with gastric distension and a delayed emptying of the stomach. The same TLESR feedback loop is responsible for normal belching, but GERD patients have acidic refluxate in addition to belched gas.
Stress reflux is another mechanism for producing reflux, wherein excessive intra-abdominal pressure squeezes the stomach to such an extent that the normal pressure generated by the LES and crural diaphragm is insufficient to prevent back-flow.
The cause of gastro-esophageal reflux in certain other individuals may be due to a LES resting tension that is abnormally low (i.e. LES hypotension). Typically, these individuals have erosive esophagitis, and approximately 70% of them have a hiatal hernia. Thus, for those individuals with a hiatal hernia, the hypotension of the LES is exacerbated by the displacement of the LES relative to the diaphragm, which would have normally provided additional external sphincter-like support. Apparently, in individuals with a hypotensive LES, the acidity of repeated reflux damages the ability of the LES to generate pressure, and the loss of that pressure promotes a vicious cycle whereby the loss of pressure produces more reflux acid to damage the LES. Because the pressure differential between the LES and stomach is relatively low in these individuals, back-flow of the contents of the stomach to the esophagus is more likely to be a constant, rather than a transient problem.
A certain amount of reflux is present even in normal individuals, but it is not sensed because refluxed acid is neutralized by bicarbonate-rich saliva, which is brought to the gastro-esophageal junction by peristaltic movement of the esophagus. Therefore, if peristaltic movement in the esophagus is impaired, failure of the reflux clearance mechanism may cause the patient to sense the reflux, even if the anti-reflux barrier is functioning normally.
The actual sensation of reflux (i.e., heartburn or esophageal pain) is thought to be sensed directly by chemo-receptors in the esophagus, or sensed indirectly as tissue damage via inflammatory mediators. It is estimated that even for individuals with GERD, less than 5% of reflux events (pH<4) are sensed as heartburn. However, in some patients, the sensory mechanisms may be defective because those individuals may sense heartburn even though no reflux is present. Some patients may also be hypersensitive to the refluxed material, exhibiting a lower than normal threshold for esophageal pain and abnormally large and prolonged neurological response to a given reflux stimulus.
In any case, esophageal pain is likely to be modulated by the detailed composition of recently ingested food, for example, because fatty foods are more likely to produce heartburn, and their digestion stimulates production of neurotransmitters, hormones, and peptides that may act on the nervous system. Such neuromodulators would act in concert with less specific stimuli that may also play a role, such as psychological stress and anxiety related to anticipation of heartburn, as well as excess sympathetic and diminished parasympathetic tone in the autonomic nervous system.
The severity of damage associated with reflux also depends on the nature of the material that is refluxed. If the contents of the stomach are excessively acidic, this will exacerbate the effects of any reflux. Such excessive acidity is ordinarily due to the nature of the food in the stomach rather than to hyper-secretion of gastric acid by the stomach. The potential exposure to reflux acid is a function of the time that food spends in the stomach, and this is in turn a function of the rate of gastric emptying. There is also a tendency in patients with advanced GERD to reflux material to the esophagus that had been previously refluxed from the intestine to the stomach (douodenogastroesophageal reflux or DGER).
The tissue in the vicinity of the gastro-esophageal junction has mechanisms for counteracting potential damage due to reflux and for healing any residual damage. They include barriers within the esophageal tissue to the diffusion of acid and pepsin. Such barriers are anatomical and do not appreciably involve the secretion of a mucin gel barrier. Other defense mechanisms include buffering to maintain intracellular pH, blood circulation to remove damaging substances, and inflammatory responses. If these defense and repair mechanisms are impaired, progression of GERD may be expected to occur. Any therapy for GERD should have as one of its objectives respite from reflux, giving normal defense and repair mechanisms time to be effective.
The typical patient with GERD has an initial complaint of heartburn, acid regurgitation, or reflux-related chest pain. Effortless regurgitation of acidic fluid, especially after meals and worsened by stooping or a supine posture, is particularly suggestive of GERD. According to an international consensus, patients may then be diagnosed as having GERD based on the typical symptoms alone [Nimish VAKIL, Sander V. van Zanten, Peter Kahrilas, John Dent, Roger Jones, and the Global Consensus Group. The Montreal Definition and Classification of Gastroesophageal Reflux Disease: A Global Evidence-Based Consensus. Am J Gastroenterol 2006; 101:1900-1920]. The first line of therapy for mild GERD is lifestyle changes (avoidance of alcohol, chocolate, fatty foods, etc.; weight loss; elevation of the head of the bed), over-the-counter antacids and foam barriers such as Gaviscon for short-term relief, H2 antagonists for longer term relief, and chewing gum to promote saliva production. If this first line of therapy is not successful, the patient may undergo a trial one to two month treatment with a proton pump inhibitor (PPI), such as esomeprazole, that would reduce the acidity of the reflux.
Patients who are difficult to treat may then be referred to a gastroenterologist for further evaluation and treatment. Ordinarily, upper gastrointestinal endoscopy will first be performed by the gastroenterologist in order to identify visual signs of erosion in the region of the gastroesophageal junction and to determine whether Barrett's metaplasia is present. Biopsies are ordinarily performed only to confirm the presence of Barrett's metaplasia. If esophagitis is found, the patient may continue treatment with different types or doses of proton pump inhibitors.
If the endoscopy results are negative, esophageal manometry may be performed to evaluate esophageal peristalsis and to confirm sphincter position and activity. For patients having a problem primarily with transient LES relaxation, therapy with the GABA agonist baclofen might be tried. Patients may also undergo 24 hour pH testing on proton-pump-inhibitor therapy, in consideration of possible diagnoses other than GERD, such as achalasia. To determine whether non-acid reflux may play a role in patients with proton-pump-inhibitor-resistant reflux symptoms, chronic unexplained cough, or excessive belching, intraluminal impedance tests may also be performed.
GERD is a chronic condition, and after medication for its treatment is stopped, the GERD symptoms will return within a few months in most patients. Some patients therefore prefer a potentially permanent surgical treatment for GERD in lieu of a lifetime of medication. Surgery may also be indicated for the subset of patients for which GERD medications are ineffective, or for patients who cannot tolerate use of those medications because of their association with enteric infections, interference with calcium metabolism, or other side effects. Surgery may also be indicated for patients who have persistent problems associated with regurgitation, notwithstanding successful pharmaceutical treatment of heartburn.
The rationale for a surgical treatment for GERD is that the surgery corrects anatomical defects that are associated with GERD—by moving a hiatal hernia back into the stomach, closing the hiatus of the diaphragm, and strengthening the tissue so as to prevent reoccurrence of a hiatal hernia. The most common such surgery is known as a 360 degree Nissen fundoplication, in which the upper part of the stomach is wrapped (plicated) around the lower end of the esophagus and stitched in place. The surgery may now be performed laparoscopically [C. Daniel SMITH. Antireflux Surgery. Surg Clin N Am 88 (2008) 943-958].
However, disadvantages of fundoplication surgery include the cost of the surgery, plus risks and complications that are associated with surgery in general, such as infection and reaction to anesthesia. Complications can also occur after anti-reflux surgery, and many patients over time will continue to require anti-reflux medications. Such complications include “gas bloat syndrome”, dysphagia (pain with swallowing and persistent feeling that something is stuck in the esophagus), dumping syndrome, excessive scarring, and rarely, achalasia. The fundoplication can also come undone over time in about 5-10% of cases, leading to recurrence of symptoms.
There are also special types of fundoplication surgery, but their use is generally limited to patients with special conditions [Derick J. CHRISTIAN, Jo Buyske. Current Status of Antireflux Surgery. Surg Clin N Am 85 (2005) 931-947]. Another type of anti-reflux surgery inserts a C-shaped toroidal ring of silicon around the outside of the esophagus and stomach, at the gastro-oesophageal junction (the Angelchik prosthesis). Although some 25,000 Angelchik prostheses have been inserted worldwide, its use has been discontinued due to problems including dysphagia and migration of the device with erosion attributable to the prosthesis. Nevertheless, such devices are still under development [U.S. Pat. No. 4,271,827, entitled Method for prevention of gastro esophageal reflux, to ANGELCHIK; Patent publication US20060276812, entitled Dynamic reinforcement of the lower esophageal sphincter, to HILL et al.; US20100076573, entitled Methods and apparatus for treating body tissue sphincters and the like, to KUGLER et al]. Another type of surgery, intraluminal valvuloplasty, is based on the premise that augmentation of the acute Angle of His and increasing the length of the esophagus will prevent GERD. [Charles J. FILIPI, Kenan M. Ulualp, et al. The Future: Endoscopic antireflux repair via the endo-organ approach. Seminars in Laparoscopic Surgery 2 (Number 1, 1995): 66-73; J AW BINGHAM. Evolution and early results of constructing an anti-reflux valve in the stomach. Proc. Roy. Soc. Med. 67 (1974):4-8; Patent publications US20040243223 and US20080228285, entitled Transoral endoscopic gastroesophageal flap valve restoration device, assembly, system and method, to KRAEMER et al.; and US20100049221, entitled Tissue fixation devices and assemblies for deploying the same, to BAKER et al.]. However, although such special surgical methods have been known for many years, problems associated with their use have prevented their widespread adoption.
Electrically-controlled prosthetic devices that replace a failed natural sphincter are also under investigation [Patent publication No. US20090259315, entitled Electroactive polymer based artificial sphincters and artificial muscle patches, to BANIK; US20090259093, entitled Artificial sphincter with piezoelectric actuator, to BHAT et al.; Olaf RUTHMANN, Sabine Richter, et al., The first teleautomatic low-voltage prosthesis with multiple therapeutic applications: a new version of the German artificial sphincter system. Artificial Organs 34 (8):635-641 (2010)]. However, these methods are too new to assess the likelihood of their utility.
Endoscopic techniques for the treatment of GERD have been developed as alternatives to medication or surgery. These techniques include the delivery of radiofrequency energy to the gastrooesophageal junction (Stretta), injection of bulking agents (Eneryx), implantation of a bioprosthesis (Gatekeeper) into the LES, and suture plication of the proximal gastric folds (Endocinch, Endoscopic Plication System). Each of these endoscopic techniques may decrease reflux symptoms, improve quality of life, and decrease the need for anti-secretory medications. However, after performing such endoscopic treatments, LES pressure rarely increases, pH normalizes in only 30% of patients, and even mild esophagitis heals infrequently. Furthermore, most insurance does not cover the cost of endoscopic anti-reflux procedures for the treatment or management of gastroesophageal reflux disease (GERD) because they are still considered experimental, investigational or unproven [D. CHEN, C. Barber, P. McLoughlin, P. Thavaneswaran, G. G. Jamieson and G. J. Maddern. Systematic review of endoscopic treatments for gastro-oesophageal reflux disease. British Journal of Surgery 2009; 96: 128-136; Julius SPICAK. Treatment of Gastroesophageal Reflux Disease: Endoscopic Aspects. Digestive Diseases 2007; 25:183-187; Alfonso TORQUATI, William O. Richards. Endoluminal GERD treatments: critical appraisal of current literature with evidence-based medicine instruments. Surg Endosc (2007) 21: 697-706. Gary W. FALK, M. Brian Fennerty, and Richard I. Rothstein. AGA Institute medical position statement on the use of endoscopic therapy for gastroesophageal reflux disease. Gastroenterology 2006; 131:1313-1314; Syed-Mohammed JAFRIA, Gaurav Aroraa, and George Triadafilopoulos. What is left of the endoscopic antireflux devices? Current Opinion in Gastroenterology 2009, 25:352-357; F. PACE, G. Costamagna, R. Penagini, A. Repici, and V. Annese. Review article: endoscopic antireflux procedures—an unfulfilled promise? Aliment Pharmacol Ther 27, 375-384 (2008)].
Although currently available endoscopic methods have had only limited success, the option to have some other form of endoscopic treatment would nevertheless be attractive to patients with GERD who have not been successfully treated with medication, but who are not suitable candidates for surgical treatment. It is therefore an objective of the present invention to provide an improved endoscopic treatment for patients with GERD. In particular, it is an objective of the present invention to provide embodiments of improved endoscopically implanted prosthetic valves and valve-retainers that can significantly reduce the symptoms of reflux in GERD patients. It is also an objective of the present invention to provide treatment for different types of patients with GERD. Yet another objective is to present improved methods for implanting such valves and valve retainers.
Current medical tests to evaluate the pathophysiology of a patient with GERD are expensive, must ordinarily be performed one after the other to provide the comprehensive data that are needed to make a proper diagnosis, and may be inconclusive in regards to their recommendation of which alternate therapeutic strategy to follow. The preferable test would monitor the patient continuously for one or more days, because a patient's GERD symptoms may be intermittent. Accordingly, there is need in the art for ambulatory monitoring devices that can measure multiple GERD-related physiological parameters, thereby providing a prompt and more comprehensive evaluation of the causes of a patient's GERD symptoms, as well to suggest the most suitable therapeutic strategy for treating the patient. An objective of one embodiment of the present invention is therefore to provide such an improved monitoring device. In particular, an objective of one embodiment of the invention is to provide a monitoring device that will simulate and evaluate the potential performance of the above-mentioned improved endoscopically implanted prosthetic valves and valve-retainers, before they are implanted permanently.